Over the last decades, convincing evidence has demonstrated a central role of hypoxia inducible factor (HIF) in mammalian oxygen homeostasis. As such, HIF-driven responses are tailored towards adaptation to limited oxygen availability and restoring adequate tissue oxygen levels. More recently, several studies also implicated HIF in transcriptional coordination of inflammatory responses. However, the role of HIF during acute lung injury (ALI) is unknown. Preliminary data from stretch exposure of pulmonary epithelia demonstrates HIF stabilization in vitro. Moreover, in vivo studies of ALI show a protective role of epithelial HIF signaling. Therefore, we hypothesize that HIF-1 is stabilized during ALI, and dampens lung inflammation and tissue injury. Three specific aims were designed to address novel roles for HIF in ALI. In the first aim, we propose to study mechanisms of mucosal HIF stabilization during cyclic mechanical stretch exposure in vitro, or during ALI in vivo. In the second aim, we will study the role of mucosal HIF in regulating lung inflammation and leukocyte trafficking during ALI. In the third aim, we will study the role of mucosal HIF during the resolution phase of ALI. These studies will shed new light on endogenous pathways that regulate lung inflammation and pulmonary injury. Targeting such pathways will lay the groundwork for novel and specific therapeutic approaches in the treatment of ALI, which are urgently needed to improve morbidity and mortality of critical illness. PUBLIC HEALTH RELEVANCE: These studies will lay the groundwork for novel and specific therapeutic approaches in the treatment of acute lung injury.